Molecular Modeling Studies on Vinblastine Binding Site of Tubulin for Antimitotic agents

Document Type : Research Paper

Authors

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Abstract

Medicinal chemistry depends on many other disciplines ranging from organic chemistry and
pharmacology to computational chemistry. Typically medicinal chemists use the most
straightforward ways to prepare compounds. The validation of any design project comes from the
biological testing.
Studies of the binding site of vinblastine by a single cross—linking experiment identified it as
being between residues 175-213 in 13—tubulin.These polypeptide residues are in the region of
lateral or longitudinal contacts of protofilaments on the microtubule in the absence of a ligand. In
the presence of vinblastine or other active vinca alkaloids a kink is formed that disturbs normal
microtubule formation and favors depolymerization.
In an effort to understand the conformational preferences that may be attributed to stereoelectronic
effects, a number of computational chemistry studies carried out. Molecular mechanics, Monte
Carlo, Molecular Dynamics and Langevin calculations using the AMBER force field performed
on vinblastine .These results show the minimized structure of vinblastine, calculated potential
energy for important dihedral angles, and the effect of temperature on geometry of optimized
structure

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